We propose to continue the follow-up of the Health Professional's Follow-up Study, a cancer epidemiology cohort of 51,529 men enrolled in 1986 when they were 40 to 75 years of age. The cohort is currently supported as part of a Program Project; consistent with NCI policy, we are now applying for support of the infrastructure through a cooperative agreement. The cohort includes a biorespository with DNA samples from 35,000 participants, plasma from 18,000, nails from 33,000, and tumor tissue from approximately 70% of incident colon, prostate, and other important cancers. In this cohort, smoking, weight, medication use, and medical diagnoses have been updated every 2 years and information on diet and physical activity has been updated every four years. Much other valuable exposure information is collected. Follow-up of the cohort has been approximately 94% complete at each of the 2-year follow-up cycles and ascertainment of deaths is at least 98% complete. This cohort has been highly productive; 341 papers have been published during the current funding cycle or are in press. Novel findings include the identification of modifiable risk factors that account for one third of aggressive prostate cancer; strong evidence based on plasma levels, germ line DNA, and gene expression in tumor tissue that vitamin D is importantly involved in risk of death from prostate cancer; and roles of specific diet factors and physical activity after the diagnosis f colorectal and prostate cancer in survival. This cohort has also contributed to 19 cancer-related consortia during this funding period and has an active data sharing component. The HPFS is unique as the largest cancer cohort in men with many repeated measures of exposure over more than two decades, which provides a powerful view of realistic latent periods for carcinogenesis and the opportunity to examine both pre-and post-diagnosis determinants of survival from cancer. Because of the massive, detailed data and biological samples already in hand, the nearly complete ascertainment of incident cancers with high rates of tissue acquisition, and the entry of the younger members of the cohort into the age of maximal cancer incidence, this cohort will be even more fruitful scientifically during the next five years.